A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T‐Cell Acute Lymphoblastic Leukemia

Abstract

Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting‐therapy efficacy remains unexplored. Here, an L‐phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T‐cell acute lymphoblastic leukemia (T‐ALL) by inhibiting myeloid‐derived suppressor cells (MDSCs) in T‐ALL murine model. Stable‐isotope tracer and in vivo drug distribution experiments show that T‐ALL cells and MDSCs have enhanced cellular uptake of L‐phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN‐Dox) specifically targets T‐ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN‐Dox has reduced cardiotoxicity and myeloablation side effects in treating T‐ALL mice. Mechanistically, MRIAN degrades into L‐phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T‐ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin

“…In addition, pharmacological blockade of FATP2 expression in MDSCs reduced lipid accumulation, decreased ROS levels, attenuated the immunosuppressive activity of MDSCs, and reduced PD-L1 expression on immune cells, thereby enhancing the effect of tumor immunotherapy [ 136 ]. A recent study found that metabolic reprogramming of the immunosurveillance-activating nanodrug-assembled doxorubicin (MRIAN-Dox) inhibited M2-type pyruvate kinase (PKM2) activity and reduced ROS levels in MDSCs in a T-cell acute lymphoblastic leukemia (T-ALL) mouse model, thereby interfering with their immunosuppressive function and increasing their differentiation to normal bone marrow cells [ 137 ].…”

The prognostic value and therapeutic targeting of myeloid-derived suppressor cells in hematological cancers

“…Studies also demonstrated an enhanced cellular uptake of MRIAN in T-ALL cells and MDSC compared to normal hematopoietic cells and progenitors. MRIAN assembled to doxorubicin (MRIAN-Dox) demonstrated an enhanced anti-tumor efficacy and reduced toxicity profile (including cardiotoxicity and myeloablation side effects) in T-ALL mice; indicating its therapeutic potential as metabolic modifier to target MDSC ( 77 ).…”

Fructose‐Derived Levan Nanoparticles Protect Against Osteoarthritis by Directly Blocking CD44 Activation

“…[7,8] To overcome these limitations, polymer-based nanomedicines have been developed using new materials. [9][10][11] Levan is a polysaccharide comprising a β-D-fructose polymer wherein the fructose rings are linked via β-glycosidic linkages. [12] The amphiphilic properties of levan enable micelles to be fabricated in aqueous solutions through self-assembly.…”